Project Summary More women than men are diagnosed with dementia and Alzheimer?s disease. Recent evidence suggests this may not be just because women live longer; some risk factors for dementia may affect men and women differently. Type 2 diabetes (T2D) is a major risk factor for dementia. It affects about 26% of the population over the age of 65 and increases the risk for dementia by 50-60%. Recent studies show T2D may be a bigger dementia risk for women than men, and estrogen levels may be important in the increased risk. One hypothesis for how diseases like T2D raise the risk of dementia is that they may change the kinds of fuel the body uses at the cellular level to generate energy. Normally, brain cells rely on glucose for fuel. We are now learning that brain cells affected by age, stress, or diseases like T2D may also use other fuels. Ketone bodies, which are derived from fats, appear to be an important alternate fuel source for the brain. Interestingly, estrogen acts on the same energy pathways as T2D and estrogen may interact with T2D to substantially increase the risk of dementia in women. A recent study from France found that women who had T2D and were also in the top 25% for natural levels of estrogen in their blood had 14 times the risk for dementia compared to T2D women with lower estrogen. Two papers in a large group of American women showed that women with T2D who randomly received estrogen therapy had an increased risk for dementia and lower brain volumes. The interaction between T2D and estrogen therapy can be interpreted as fitting with the ?healthy cell bias? (HCB) theory for estrogen. Estrogen enhances glucose use while slowing the use of ketones for cellular energy. The HCB theory posits that in healthy brain cells using glucose as their main fuel, the glucose- enhancing properties of estrogen enhance the energy capability of the cells and the action of estrogen is protective. However, in cells challenged by stress, aging, or disease (such as T2D) brain cells may begin to rely on other fuel sources such as ketone bodies to meet the heavy energy needs of the brain. In this case, estrogen?s effects of suppressing ketone use may deprive cells needed energy, posing a risk to brain health. We propose to directly test in humans the hypothesis that the HCB theory explains the population-level observation that estrogen interacts with T2D to increase dementia risk. We propose to collect positron emission tomography (PET) scans that measure uptake of ketones and glucose in women with and without T2D before and after 12 weeks of using an estrogen patch. This is an innovative, proof-of-concept study that uses new techniques to explore a novel, modifiable interaction between estrogen and a common disease on dementia risk in women.